Project Summary: Rates of Cannabis Use Disorder (CUD) have doubled over the last ten years in the US. Although increasing, overall rates of cannabis use and CUD are still lower among women relative to men. However, epidemiological reports document a telescoping effect; women transition from first use to CUD at a faster rate than men. Preclinical studies with laboratory animals demonstrate that relative to males, females are more sensitive to the reinforcing effects of cannabinoids, perhaps explaining the accelerated progression to CUD observed in the epidemiological reports. To date, no studies have prospectively probed cannabis?s sex- dependent differences in abuse-liability in humans. To understand cannabis?s acute effects that underlie the accelerated trajectory to CUD observed in women, the proposed study will compare the dose-dependent effects of smoked cannabis on endpoints directly associated with abuse-liability between light- and heavy- cannabis using men and women, including positive subjective effects and cannabis self-administration. In addition to abuse-related endpoints, understanding sex differences in the analgesic responses to smoked cannabis have significant public health implications. Nearly 50% of medical cannabis users are women, with pain cited as the primary indication for which treatment is sought. Thus, assessing both the abuse liability and analgesic efficacy of cannabis as a function of sex is of critical importance. Preclinical studies point to three factors that contribute to sex-dependent responses to ?-9- tetrahydrocannabinol (THC) and other cannabinoid 1 receptor (CBR1) agonists; 1) estradiol increases the sensitivity to CBR1 agonist abuse-related effects, 2) pharmacokinetics (pK) of THC differ, with females exhibiting faster conversion from THC to its primary psychoactive metabolite than males and 3) enhanced development of tolerance to the antinociceptive effects (but not other endpoints) in females after chronic administration. The proposed prospective clinical study will directly address sex-dependent differences in cannabis?s effects as a function of these factors. We will 1) compare the abuse-related and analgesic effects of smoked cannabis between men to women while controlling for menstrual cycle effects, 2) evaluate differences in the pK of THC and respective metabolites between men and women, and 3) investigate cannabis?s sex-dependent effects as a function of frequency of cannabis use (light versus heavy cannabis users). Specifically, healthy light (N=60, 30M, 30F) and heavy (N=60, 30M, 30F) cannabis users will be recruited for this 3-session, double-blind, placebo-controlled, laboratory study. All participants will be administered placebo (0% THC), lower (3% THC), and higher (10% THC) strengths of cannabis in counter- balanced order. Cannabis?s abuse-related effects, analgesia, and pharmacokinetics will be assessed as a function of sex and frequency of cannabis use. Findings from this study will fill a critical gap in our knowledge and be integral in understanding sex as a biological variable in predicting, preventing, and treating CUD.